Research into the biological basis of tiredness shows that both mental and
physical factors bring about that feeling of exhaustion. But where, when and
how in muscles and the nervous system does fatigue begin?
WE all know the feeling, yet the causes of fatigue have long proved hard to
identify. This is partly because the term 鈥渇atigue鈥� can describe either
physical or mental states and partly because there are many contributing
factors. However all is not lost. Within the past few years, muscle
physiologists have traced the roots of physical fatigue to events that occur
within muscle cells. And although mental fatigue is proving much more
difficult to pin down, some challenging questions are emerging from research
stimulated by a controversial condition that is known as 鈥渃hronic fatigue
syndrome鈥�, or more euphemistically as 鈥測uppie flu鈥�.
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The causes of fatigue range from changes of muscle cell biochemistry to
boredom. This makes it very difficult to study with any one method or
technique. But a useful starting point is to remember that to move our bodies
we must use skeletal muscles. Equally important to researchers is the fact
that skeletal muscle is voluntary muscle. In other words, our minds control it
directly 鈥� unlike, for instance, the involuntary muscles that move food
through our gut.
To explain physical and mental fatigue, scientists must first understand how
skeletal muscle works and then try to determine what happens when fatigue sets
in. Do the muscles themselves change? Or is it the mind鈥檚 ability to control
the muscles that changes?
Control of muscles
Brain impulses
IN PRINCIPLE, fatigue could be due to a failure occurring anywhere along the
complex route from brain to muscle called the movement pathway. This begins
with the mind鈥檚 desire to move and ends with the biochemical processes that
cause muscle cells to contract. The best understood part of the pathway begins
with nerve cells known as upper motor neurons which are found in a part of the
brain specialising in motor control, the motor cortex. The cortex is the
brain鈥檚 outer layer of nerve tissue. The motor cortex is a segment of this
layer and it acts as a gathering point for nerve impulses from several other
parts of the brain. But these impulses do not just act to trigger movement,
they also fine tune them, ensuring they are carried out accurately and in the
right sequence. The details of these control mechanisms remain poorly
understood, but neuroscientists know that the motor cortex contains a 鈥渕ap鈥� of
the various muscles of the body. This was shown dramatically in the 1930s by
the Canadian neurosurgeon Wilder Penfield. Penfield electrically stimulated
parts of the motor cortex of conscious patients. He found that during this
procedure the patient temporarily lost voluntary control of the muscles mapped
by that brain area. A patient鈥檚 arm and hand, for example, might make a
series of movements, but the patient himself would be surprised to see his arm
and hand moving as though under external control.
What happens beyond the brain? Anatomy shows that nerve fibres leave the
motor cortex, enter the spinal cord, where they finally make connections, or
synapses, with lower motor neurons. These neurons act as a further gathering
point for nerve impulses arriving from the motor cortex and other areas of the
brain (see Box 1). On leaving the spinal cord, nerve fibres from lower motor
neurons eventually make contact with muscle cells at specialised synapses
called neuromuscular junctions. When nerve impulses arrive here they act to
stimulate muscles electrically. This sets off a chain of electrical and
biochemical events known as excitation-contraction coupling.
Muscle contraction
Chemical trigger
HOW does excitation-contraction coupling work? Somehow, the electrical
excitation in the muscle cell membrane has to 鈥渢ell鈥� the tens of thousands of
protein filaments, or myofilaments, from which muscles are made to contract.
All the myofilaments must move in unison, and this explains why the membranes
of muscle cells have special deep infoldings known as T-tubules. These ensure
that the excitatory impulse reaches all parts of the cell within a few
thousandths of a second.
What happens next depends crucially on calcium 鈥� the chemical trigger for
contraction. Near to the T-tubules is a calcium store called the sarcoplasmic
reticulum. When an electrical impulse travels along a T-tubule, it alters the
shape of a protein embedded in the sarcoplasmic reticulum. And this in turn
unlocks the molecular equivalent of a gate through which calcium can escape.
As a result, muscle cells become temporarily flooded with calcium.
The main effect of the calcium is to change dramatically the character of a
key muscle protein known as troponin. Without calcium, these troponin
molecules behave like chaperones, preventing filaments made from the two main
muscle proteins, actin and myosin, from interacting. In this way, troponin
prevents the muscle from contracting.
But calcium changes everything. It alters the shape of troponin, switching the
protein from a diligent chaperone to an indifferent bystander. Immediately,
neighbouring filaments of actin and myosin begin to interact, allowing the
filaments to slide past each other 鈥� a relative motion that lies at the
molecular heart of muscle contraction.
The sliding motion is made possible by the unusual structure of myosin
molecules. They have fibrous 鈥渢ails鈥� that bind together to form the so-called
thick filaments of muscle fibres. Each myosin molecule also has an arm, or
cross-bridge, that stretches out from the thick filament, brandishing a
globular 鈥渉ead鈥�. When troponin binds calcium, its shape change allows myosin
heads to interact with molecules of actin which bind together to make up thin
filaments. The myosin head is called a cross-bridge because it links thick and
thin filaments during contraction.
Knowing this molecular architecture makes it easier to understand how a
biochemical cycle 鈥� the cross-bridge cycle 鈥� can lead to muscle contraction.
First, myosin and actin must bind. Next, cross-bridge flexion causes thick and
thin filaments to slide past each other. Finally, cross-bridges release the
thin filament, and the cycle repeats itself.
Where does the energy for this cycling come from? The answer lies with
adenosine triphosphate, or ATP, the chemical fuel that is generated by the
burning of oxygen inside organelles known as mitochondria. ATP is needed to
release myosin from actin, tepriming it so that another cycle can begin.
Provided there is sufficient ATP in the muscles, cross-bridges continue to
cycle for as long as the levels of calcium remain high.
But as soon as the motor nerves stop firing, the sarcoplasmic reticulum shuts
down its release of calcium and pumps calcium back into its stores. As calcium
levels fall, troponin loses its calcium, changes back to its 鈥渞esting鈥� shape
and starts chaperoning actin and myosin again, keeping them from interacting.
The muscle relaxes. Every time you contract a muscle anywhere in your body,
this entire chain of events is enacted within fractions of a second.
Muscular fatigue
Flagging strength
MUSCLE physiologists define fatigue in two ways: as a failure to maintain
force in a prolonged contraction or as a failure to re-attain force in
repeated contractions. The first of these describes the gradual sagging of
your arm as you begin to lose in arm wrestling; the second your gradual
inability to do press-ups after the first ten or so. But why do these types of
fatigue happen?
A milestone in understanding fatigue came in the early 1950s, when the British
physiologist Patrick Merton studied the development of fatigue in a small
muscle of the human hand (see Box 2). His experiments showed for the first
time that, in some circumstances, the biological basis of fatigue lies in the
muscle itself. This discovery implied there was a biological limit to what
muscles could achieve, even with the highest possible levels of psychological
motivation and electrical stimulation of muscle cells. Today researchers can
elaborate on this story. They now know that there are two possible ways of
explaining this type of fatigue. When muscles are used in a prolonged
contraction, the amount of calcium released by the sarcoplasmic reticulum may
begin to fall. Alternatively, the myofilaments may become progressively less
responsive to calcium.
The strongest evidence for these causes of fatigue comes from a technique
known as calcium imaging. This involves injecting a muscle cell with a
compound that fluoresces when it comes into contact with calcium. The more
calcium there is in a particular region of a cell, the more intense is the
fluorescence. Researchers can use this technique to see what happens inside a
muscle cell during a prolonged contraction. At first the calcium is smoothly
distributed within the cell. But later, it begins to form a banded pattern, in
which the concentrations of calcium peak at the edges of the cell and tail off
towards the centre.
These bands seem to be caused by ionic changes in the T-tubules. Electrical
impulses depend on sodium and potassium ions being at specific concentrations
inside and outside cell membranes. If the balance of these ions changes,
membranes may find it harder to conduct an electrical impulse. This is what
happens to the T-tubules: as the muscle tires, they become progressively less
efficient conductors and therefore stimulate the central sarcoplasmic
reticulum less and less. This in turn means that less force is produced by
this part of the muscle cell and the muscle fatigues. But the sarcoplasmic
reticulum near the surface membrane continues to function almost normally.
Hence the banded calcium distribution: normal near the surface, falling
towards the centre of the cell.
A different pattern is seen when fatigue is produced by repeated, short
contractions. In this case, calcium levels fall uniformly across the cell. The
entire sarcoplasmic reticulum seems to grow tired of releasing calcium. Why it
does so is not yet fully understood. But evidence points to certain metabolic
changes that occur when muscles are repeatedly used. These changes include the
effects of the breakdown of ATP and creatine phosphate (another substance that
stores energy) to products such as adenosine diphosphate, or ADP, phosphate
ions and creatine. Muscles also produce lactic acid during heavy activity.
Several of these metabolic changes may act together to slow the release of
calcium during muscle fatigue, according to recent studies. The changes also
affect the molecular pump which moves calcium back into the sarcoplasmic
reticulum, slowing muscle relaxation during fatigue. But it is still too early
to draw any final conclusions.
More straightforward are the effects of metabolic changes on the myofilaments.
Since phosphate and lactic acid weaken the response of myofilaments to
calcium, both probably contribute to fatigue. Phosphate blocks cross-bridge
cycling, while lactic acid interferes with muscle contraction in several ways
鈥� in particular by reducing troponin鈥檚 appetite for calcium. Since troponin
acts as the on-off switch for cross-bridge cycling, the muscle cannot produce
as much force.
Outside the muscle
Disorder controversy
MUSCLE physiology cannot explain all forms of fatigue. Just as important in
many cases are psychological factors. Sometimes physical and mental factors
combine to make us feel tired. We may give up running for a bus both
because our muscles are tired and because we have lost interest. In other
situations failing motivation may be paramount. If you are asked to do a
single, repetitive task, on a production line for example, your interest and
performance will eventually decline. Industrial psychologists have long
appreciated the advantages of rotating workers.
But understanding why motivation flags is far from easy. We know very little
about the biology of the mental commands that drive 鈥� or fail to drive 鈥�
movement. The task of tracing these origins may prove harder than anyone would
have imagined a few years ago, because it is fast becoming clear that there is
no one motor 鈥渃ommand centre鈥� in the brain. Neuroscientists are finding that
upper and lower motor neurons are influenced by networks of neurons in other
parts of the brain 鈥� for example, inside brain structures known as the basal
ganglia and cerebellum. This 鈥渄istributed鈥� quality of motor control means that, for the time being,
researchers must settle for psychological rather than neural explanations of
motivation.
In some cases, fatigue is a symptom of another condition or
illness. Anxiety, depression and sleep deprivation can all produce fatigue.
And everyone knows the feeling of lethargy that can be produced by a bad cold.
But many other conditions cause a similar response which seems to be due to
the rapid release of acute phase proteins into the bloodstream. These proteins
are made by the liver and 鈥� by unknown mechanisms 鈥� cause lethargy, fatigue
and sleep, symptoms which may help to conserve resources for overcoming
disease.
Tiredness is also a common symptom of heart and lung diseases. Without
adequate circulation and oxygenation of the blood, muscles cannot function
efficiently during exercise.
In a rare condition called myasthenia gravis, nerves gradually lose the
ability to transmit electrical impulses to muscles. The problem is caused by
muscle cells gradually losing receptors for the molecule acetylcholine (which
carries messages from one side of the neuromuscular junction to the other).
Sufferers rapidly become tired when they exercise. This fatigue can usually be
helped by drugs which prolong the action of acetylcholine.
In recent years, a condition called chronic fatigue syndrome has caused a
storm of controversy. In this illness, severe fatigue affects both mental and
physical functioning. Initially, doctors and researchers presumed that the
cause was an abnormal reaction to a virus. But subsequent studies failed to
uncover any evidence of viral infections in many cases, leading some
researchers to doubt that the condition qualified as a diagnosable syndrome.
The picture is confused by the fact that psycho-social factors such as anxiety
and depression play a major part in many patients with severe fatigue.
That said, there is growing evidence that many people do indeed suffer from
severe and disabling fatigue with no known cause. Measurements of muscle
function in these patients show no signs of abnormalities, indicating that the
problem is located in the nervous system. Patients often have other symptoms
such as sleep and bowel disturbances, palpitations and night sweats. Because
of this, many researchers now believe that a subtle problem with the
hypothalamus may be at the heart of chronic fatigue syndrome.
Although no specific agent has yet been identified, many people believe
that in these special cases, abnormal reactions to viruses could well be the
underlying cause. Since the causes of chronic fatigue syndrome remain unknown, the principle aim
of treatment is to relieve symptoms.
The nervous systems controlling movement are complex, and fatigue can mean many different things. But despite this, a
combination of approaches gives us a detailed, if not yet complete, picture of
the biological and psychological processes behind fatigue. In highly motivated
individuals such as athletes, the fundamental limits on muscular achievement
appear to be within muscle cells. The main way to improve performance is to
increase the size and efficiency of muscles by training.
The precise nature of the molecular mechanisms which enable muscles to expand
and strengthen with training are still unclear. But athletes and scientists
alike have long known that the type of fibre in a muscle can change depending
on how the muscle is used. There are three basic types of muscle fibre:
鈥渇ast鈥�, 鈥渟low鈥� and 鈥渋ntermediate鈥�. If you lift weights, you will develop
鈥渇ast鈥� fibres; if you run marathons, you will develop 鈥渟low鈥� fibres.
Researchers are now trying to unravel the hormones, metabolic changes and
mechanical factors that lead to the growth of specialised muscle fibres.
1. Controlling strength
LOWER motor neurons make up the final pathway for control of movement, since
all nerve signals for movement must pass through them to reach muscles. Each
lower motor neuron supplies several muscle cells within a muscle. The muscle
fibres linked to each motor neuron are called a motor unit. A muscle such as
the biceps is composed of many muscle cells, but a smaller number of motor
units.
Motor units may contain just a few, or tens to hundreds of muscle cells. Small
lower motor neurons supply small motor units, while larger neurons supply
larger motor units. This is important for muscular control because larger
motor neurons require a more intense signal to become activated. That means
weak commands tend to excite small motor units first, resulting in weak
contractions, while stronger commands excite progressively larger motor
neurons, producing stronger contractions.
The interface between the nervous system and muscle cells is the neuromuscular
junction. Here, the nerve fibre comes to a bulbous ending and the underlying
cell membrane of the muscle cell is thrown into complex folds. When a nerve
impulse arrives at the neuromuscular junction, it stimulates minute synaptic
vesicles within the nerve terminal to release their cargo of the
neurotransmitter acetylcholine.
Acetylcholine rapidly diffuses across the small gap to the muscle cell and
binds to specific receptors on the muscle cell membrane. This starts an
electrical impulse in the muscle cell membrane, beginning the process known as
excitation-contraction coupling, which culminates in the muscle contracting.
Acetylcholine is quickly removed by the enzyme acetylcholinesterase, allowing
the muscle to be switched on and off rapidly. So a single nerve impulse
excites the muscle only briefly, producing a short-lived, weak contraction
called a twitch. Descending motor signals usually cause lower motor neurons to
fire at rates of 50 to 100 impulses per second. This means that the next
impulse arrives before the muscle relaxes, increasing force even more (a tetanus). Neurons
usually fire at rates which make motor units develop maximum force. So
strength is determined more by how many motor units are active rather than how
strongly each one is pulling.
2. A classic experiment
IN THE 1950s it was not known whether muscular force was limited by descending
impulses, transmission across the neuromuscular junction or by the contractile
properties of muscle fibres themselves. Patrick Merton, a physiologist then at
the MRC Neurological Research Unit in London, approached this problem by
comparing the maximum force produced by voluntary contractions of a muscle
with that obtained by electrical stimulation of the nerve supplying the
muscle.
Merton studied the adductor pollicis muscle 鈥� the muscle you use to make your
thumb come towards the palm of your hand. In the first part of his study,
Merton compared the force of a voluntary contraction with the force of an
electrically stimulated contraction in rested muscle. Initially, he performed
the experiment on himself. This took some courage, since at the time it was
widely believed that the maximum force produced by electrically stimulated
muscles was much greater than could be achieved by voluntary effort and would
be enough to rupture tendons and even break bones.
Merton proved this idea was wrong. First, subjects pulled against a transducer
as hard as they could and the force generated was measured. Then electrical
stimuli of increasing frequency were applied to the nerve until maximum force
was reached. Finally, subjects repeated their voluntary contraction.
The results showed that the forces produced during maximal voluntary and
electrically stimulated contractions were the same, proving that descending
impulses can fully activate rested muscle. In other words, muscles have no
鈥渉idden strength鈥�. Incidentally, this experiment also disproved the old notion
that frenzied lunatics or people under hypnosis were able to suddenly develop
the strength of many by tapping unused resources.
Next Merton studied fatigue. Subjects performed a sustained maximum voluntary
contraction. After a few seconds, fatigue set in and the force slowly fell, in
spite of maximum effort from the subjects. Merton reasoned that if fatigue was
due to declining central commands, electrical stimulation of the nerve should
reverse the falling force. In fact, superimposing electrical stimuli had no
effect, showing that fatigue was developing at the muscle.
But was fatigue due to transmission failure at the neuromuscular junction or
to processes within the muscle? This was answered by measuring the electrical
activity of the muscle with electrodes placed on the skin over the muscle. The
size of these muscle action potentials is an indication of the number of
muscle fibres being activated. So, if the size of the muscle action potential
fell it would indicate failure at the neuromuscular junction. There was no
change in the size of the muscle action potential thus completing the
experiment and providing the first clear evidence that fatigue can be the
result of processes occurring entirely within muscle cells.
Further Reading
The Physiology of Excitable Cells, 3rd edition, by David Aidley (Cambridge
University Press, 1989). 鈥淩ole of excitation-contraction coupling in muscle
fatigue鈥�, by D. Allen, H. Westerblad, John Lee and J. L盲nnergren, Sports
Medicine, Volume 13, pp116-126, 1992.